Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
Cell Host Microbe. 2023 Jul 12;31(7):1154-1169.e10. doi: 10.1016/j.chom.2023.05.030. Epub 2023 Jun 5.
Targeted protein degradation (TPD), as exemplified by proteolysis-targeting chimera (PROTAC), is an emerging drug discovery platform. PROTAC molecules, which typically contain a target protein ligand linked to an E3 ligase ligand, recruit a target protein to the E3 ligase to induce its ubiquitination and degradation. Here, we applied PROTAC approaches to develop broad-spectrum antivirals targeting key host factors for many viruses and virus-specific antivirals targeting unique viral proteins. For host-directed antivirals, we identified a small-molecule degrader, FM-74-103, that elicits selective degradation of human GSPT1, a translation termination factor. FM-74-103-mediated GSPT1 degradation inhibits both RNA and DNA viruses. Among virus-specific antivirals, we developed viral RNA oligonucleotide-based bifunctional molecules (Destroyers). As a proof of principle, RNA mimics of viral promoter sequences were used as heterobifunctional molecules to recruit and target influenza viral polymerase for degradation. This work highlights the broad utility of TPD to rationally design and develop next-generation antivirals.
靶向蛋白降解（TPD），以蛋白水解靶向嵌合体（PROTAC）为例，是一种新兴的药物发现平台。PROTAC 分子通常包含一个靶蛋白配体与一个 E3 连接酶配体相连，招募靶蛋白到 E3 连接酶以诱导其泛素化和降解。在这里，我们应用 PROTAC 方法开发了针对许多病毒关键宿主因子的广谱抗病毒药物和针对独特病毒蛋白的病毒特异性抗病毒药物。对于宿主定向抗病毒药物，我们鉴定出一种小分子降解剂 FM-74-103，它可选择性地降解人类 GSPT1，一种翻译终止因子。FM-74-103 介导的 GSPT1 降解抑制了 RNA 和 DNA 病毒。在病毒特异性抗病毒药物中，我们开发了基于病毒 RNA 寡核苷酸的双功能分子（Destroyers）。作为原理验证，我们使用病毒启动子序列的 RNA 模拟物作为异双功能分子来招募和靶向流感病毒聚合酶进行降解。这项工作突出了 TPD 在合理设计和开发下一代抗病毒药物方面的广泛应用。
